Tempel, Zachary J.; Monaco, Edward A. III; Friedlander, Robert M.
As is too often the case with neurological diseases, we have limited understanding of the pathophysiologic mechanisms of spinal cord injury (SCI). This paucity of knowledge has, in turn, greatly impeded the ability of physicians, surgeons, and scientists to develop novel treatment modalities aimed at restoration of neurologic function in patients suffering these life altering injuries. In fact, severe or complete SCI still carries a rather grim prognosis with respect to neurologic recovery due to the limited ability of neurons in the central nervous system (CNS) to regenerate.
The development of novel therapies for disease processes relies critically on the thorough understanding of the disease process itself. The characteristic “CNS scar” that forms at the location of neurologic injury is well-recognized as a key obstacle to neuronal plasticity and regeneration, and ultimately, recovery of neurologic function. However, the exact details of CNS scar formation are not thoroughly characterized. Many have postulated that astrocytes are the key cell-type involved in initiating fibroblast-induced CNS scar formation and serve as a potentially important therapeutic target. In a recent article, Goritz et al (Goritz C, Dias D, Tomilin N, Barbacid M, Shupliakov O, Frisen J. A pericyte origin of spinal cord scar tissue. Science. 2011;333:238-242) present an alternate theory in their examination of the role of pericytes as the potential key cell-type involved in CNS scar formation. Therapies aimed at modulating pericyte activity following SCI could affect CNS scar formation and potentially influence neuronal plasticity. Moreover, amelioration of scar formation could be a path toward improving overall recovery of neurological function.
As the authors point out, scar formation occurs as fibroblasts are recruited to the site of injury and lay down an extensive network of extra-cellular matrix proteins, which eventually form connective tissue. However, especially for CNS injury, the pathway of initiation of fibroblast differentiation and recruitment is unclear. The authors used R26R-YFP recombined Glast-CreER transgenic mice to label a subset of pericytes (referred to as Type A pericytes) that are normally present in adult spinal cord and followed their fate following SCI. After injury, the number of Type A pericytes increased dramatically, peaking at 2 weeks then gradually decreasing until leveling off at a steady number. This is analogous to the ebb and flow of astrocyte numbers following SCI. However, the population of pericytes increased much more dramatically following SCI compared to the population of astrocytes.
Next, the investigators examined the relationship between astrocyte and pericyte populations following SCI. In normal spinal cord tissue, resident astrocytes outnumber resident pericytes 10 to 1. However, in the weeks following injury, the pericyte population increases and reverses this ration such that pericytes outnumber astrocytes by 2 to 1. In addition to changes in the abundance of pericytes, they change their location in the injury microenvironment. As angiogenesis at the site of injury occurs, Type A pericytes, which are normally encased in the vascular basal lamina, detach from vessel walls and migrate into the surrounding tissues. These cells subsequently give rise to extracellular matrix depositing stromal cells, as evidenced by a change in surface marker expression, which are responsible for scar formation.
Formation of CNS scar following SCI appears to be a local process as Type A pericytes are resident cells in normal spinal cord tissue. Finally, the authors wanted to understand how scar formation might proceed in the absence of an expanded pericyte population. By blocking the generation of pericyte progeny following SCI, they observed failure of the wound to seal off. Thus, based on this information, Type A pericytes seem to function as the key cell type responsible for CNS scar formation following SCI.
Due in large part to advances in genetics, proteomics and molecular biology, scientists and physicians have enhanced the understanding of the pathophysiology of complex disease processes. Disease processes are rapidly being broken down to the molecular level. Understanding the critical steps in a disease process permits the development of targeted therapies. Surgical intervention is only a minor part of the comprehensive care required in patients with severe or complete SCI. This work by Goritz et al sheds new light on an old problem. The development of pharmaceuticals or antibodies aimed to specifically target and modulate Type A pericytes in patients with SCI could positively affect neuronal regeneration and long-term recovery of neurologic function.
Figure. Pericytes gi...Image Tools